1. Field of the Invention
The present invention provides methods for treating heart failure improving renal function preventing or delaying the advancement of heart failure into advanced stages, and counteracting ischemia due to a myocardial infarction by providing improved methods of administering a therapeutically effective amount CGRP as a controlled release formulation.
2. Description of the Prior Art
Heart failure is a complex clinical syndrome that can result from any structural or functional cardiac disorder that impairs the ability of the ventricle to fill with or eject blood, and the heart works less efficiently than it should. Heart failure is characterized by specific symptoms (e.g., dyspnea and fatigue) which may limit exercise tolerance and signs (e.g., fluid retention) which may lead to pulmonary congestion and peripheral edema. Both abnormalities can impair the functional capacity and quality of life of affected individuals, but they may not necessarily dominate the clinical picture at the same time. Because not all patients have volume overload at the time of initial or subsequent evaluation, the term “heart failure” is preferred over the older term “congestive heart failure.”
The clinical syndrome of heart failure may result from disorders of the pericardium, myocardium, endocardium, or great vessel. For example, common causes of heart failure include: narrowing of the arteries supplying blood to the heart muscle (coronary heart disease); prior heart attack (myocardial infarction) resulting in scar tissue large enough to interfere with normal function of the heart; high blood pressure; heart valve disease due to past rheumatic fever or an abnormality present at birth; primary disease of the heart muscle itself (cardiomyopathy); defects in the heart present at birth (congenital heart disease) and infection of the heart valves and/or muscle itself (endocarditis and/or myocarditis or pericarditis). The majority of patients with heart failure have symptoms due to an impairment of left ventricular function. Each of these disease processes can lead to heart failure by reducing the strength and efficiency of the heart muscle contraction, by limiting the ability of the heart's pumping chambers to fill with blood due to mechanical problems or impaired diastolic relaxation, or by filling the chambers with too much blood.
Renal blood flow is also an important factor in the development of the clinical syndrome of heart failure. It is a determinant of some important neurohormonal responses and of salt and water retention. Renal blood flow is reduced in patients with HF, and many patients with HF will also eventually develop renal failure.
There are four stages of heart failure recognized by the American College of Cardiology Guidelines for the Evaluation and Management of Chronic Heart Failure in the Adult. Stage A refers to patients who are at high risk for developing heart failure but have no identified structural or functional abnormalities of the heart and have never shown signs or symptoms of heart failure. If needed, Stage A patients are prescribed ACE inhibitors to lower blood pressure and reduce the heart's work load. Stage B refers to patients who have developed structural heart disease strongly associated with the development of heart failure but have never shown signs or symptoms of heart failure. Stage B patients are typically prescribed ACE inhibitors and beta-blockers that decrease myocardial oxygen demand and thereby ischemia, and reduce heart rate and cardiac work. Stage C refers to current or prior symptoms of heart failure associated with underlying structural disease. Management of HF at Stage C can involve a triple or quadruple drug therapy that includes ACE inhibitors, beta-blockers, diuretics, and Digitalis. Stage D refers to patients with advanced structural heart disease and marked symptoms of heart failure at rest despite maximal medical therapy, requiring specialized intervention. Since HF is a terminal condition, mid and end-stage BF (Stages C and D, respectively) treatment focuses on alleviating symptoms and increasing the patient's quality of life such that they can continue to live a relatively active lifestyle. Successful management of the progression of heart failure and effective treatments to relieve heart failure symptoms are determined by monitoring increases in the heart's ejection fraction, decreases in dyspnea, and changes in the frequency and/or severity of heart failure symptoms. However, while current end-stage drug therapies such as Dobutamine or Milrinone increase the patient's quality of life, they also have been shown to increase mortality.
It is estimated that about four million people in the United States suffer from various degrees of heart failure. Although heart failure is a chronic condition, the disease often requires acute hospital care. Patients are commonly admitted for acute pulmonary congestion accompanied by serious or severe shortness of breath. Acute care for HF accounts for the use of more hospital days than any other cardiac diagnosis, and consumes in excess of seven and one-half billion dollars in the United States annually.
Current research into the treatment of chronic heart failure is focused on providing cardioprotection, myocardial tissue salvage by minimizing or reducing infarction size, and preventing reperfusion injury. Many current drug therapies for treating heart failure address specific clinical aspects associated with myocardial infarction, such as anti-platelet/fibrinolytic, anti-inflammatory, and antioxidant activities. Such drugs include ACE inhibitors to prevent blood vessel constriction and to increase blood flow to the body, diuretics to remove excess fluid, beta blockers to reduce heart work load, calcium channel blockers to increase the blood flow through the heart and prevent vessel constriction, blood thinners to prevent blood clots, and cardiotonics to strengthen the heart's ability to pump blood. Only a few companies to date are developing new drugs that address tissue salvage, however the effectiveness of these drugs remains to be established in the clinic. As with all drugs, these agents must be taken in doses sufficient to ensure their effectiveness. Problematically, however, over-treatment can lead to hypotension, renal impairment, hyponatremia, hypokalemia, worsening heart failure, impaired mental functioning, and other adverse conditions. Surgical treatments include angioplasty, coronary arty by-pass grafts, valve replacement, pacemakers, internal defibrillators, left ventricular assist devices, and heart transplants.
Heart failure is the number one diagnosis for hospital admissions in patients over the age of 65. More than $38.1 billion has been spent annually since 1991 on inpatient and outpatient costs and greater than $500 million on drugs to treat HF. The disorder is the underlying reason for 12 to 15 million office visits each year and 1.7 to 2.6, million hospital admissions each year. Because of the hospitalization costs required to treat a heart failure patient, the current trend is to get HF patients into outpatient care as soon as possible, often within the 48 hours of hospital admission. Specialized outpatient clinics are now available for heart failure patients. The patients typically attend the clinic between one and four times per week to receive intravenous infusions of a prescribed heart failure therapy until hemodynamic symptoms improve.
Calcitonin gene-related peptide (“CGRP”) is a 37-amino acid neuropeptide which is the most potent naturally occurring vasodilator peptide in the human body. CGRP is distributed throughout the central and peripheral nervous systems, and is found in areas that ate known to be involved in cardiovascular function (Wimalawansa, S., Critical Reviews in Neurobiology, 11:167-239 (1997)). Peripherally, CGRP is found in the heart, particularly in association with the sinoatrial and atrioventricular nodes. In addition, CGRP is found in nerve fibers that form a dense periadventitial network throughout the peripheral vascular system, including the cerebral, coronary, and renal arteries. CGRP has prominent cardiovascular effects, including vasodilation and positive chronotropic and inotropic effects, which may play an important role in normal cardiovascular function (Wimalawansa, S., Endocrine Reviews. 17:208:217 (1996)).
When administered, CGRP has pronounced cardiovascular benefits, including vasodilation, ischemic cardioprotection, reduction in infarction size due to heart attack, inhibition of platelet aggregation and smooth muscle cell proliferation which can potentially reduce the incidence of restenosis, increased renal function, and overall increased efficiency of cardiovascular functions. As a result of providing cardioprotection, minimizing reperfusion injury, and reducing infarction size, CGRP also promotes myocardial tissue salvage. CGRP also plays a role in regulating inotropy, chronotropy, microvascular permeability, vascular tone, and angiogenesis. CGRP also has significant advantages over conventional drug treatments. First, CGRP does not produce the potentially dangerous side effects, toxicity and tolerance associated with conventional cardiovascular drugs such as Nitroglycerin, Dobutamine and Natrecor. In fact, CGRP has been reported to down-regulate immune response via inhibition of cytokine release and has been safely administered to immuno-suppressed subjects without the induction of sensitivity. Second, because CGRP has multiple hemodynamic benefits, it can potentially reduce or eliminate the need for drug cocktails to maintain specific hemodynamic functions. Third, the biochemical activity of CORP is mediated through specific receptor binding sites concentrated in the heart, kidneys, and genitalia, and is known, to act on two specific CGRP receptor subtypes located on the surface of the endothelial and smooth muscle cells, respectively. Accordingly, CGRP exhibits virtually no side effects or tolerance when administered systemically.
Studies have demonstrated that acute administration of CGRP can result in increased cardiac performance and reduced systemic resistance in a number of clinical scenarios. For example, Anand, et al. (J. Am. Coll. Cardiol., 17:208-217 (1991)) reported that short-term IV infusions (10 or 20 minutes) of CGRP at rates of 0.8, 3.2, or 16 ng/kg/min (i.e., 56, 224, or 1120 ng/min based on a 70 kg subject) produced beneficial hemodynamic effects such as decreased systemic vascular resistance and increase in cardiac output, with no tachycardia observed. The study concluded that at lower doses CGRP behaves as a pure arteriolar vasodilator, where as at the higher dose CGRP acts a mixed vasodilator. Stephenson, et al. (Int. J. Cardiol., 37:407-414 (1992)) reported administration of CGRP at a rate of 600 ng/min by either a 48-hour continuous IV-infusion or 2-8 hour infusions for two consecutive days. In the continuous infusion therapy, infusion was discontinued after 28 hours in 3 out of the 6 patients due to nausea, diarrhea, and/or severe facial flushing. On the other hand, the pulsed therapy was well tolerated and was observed to improve hemodynamic functions such as left ventricular function. However, unfavorable side effects of tachycardia and neurohumoral response were also observed with the pulsed therapy. Sekhar, et al. (Am. J. Cardiol. 67:732-736 (1991) reported administration of CGRP at a rate of 8 ng/kg/min (i.e., 560 ng/min based on a 70 kg subject) by IV infusion for 8 hours. This therapy was observed to have beneficial hemodynamic effects such as decreased pulmonary and systemic arterial pressure, decreased vascular resistance and increased cardiac output. It was also observed that renal blood flow and glomerular filtration were increased during treatment. However, the hemodynamic effects were lost within 30 minutes of stopping CGRP infusion.
Chronic HF is a progressive disease. Therefore, therapies that initially seek to reduce disease progression while increasing the patient's quality of life and relieving symptoms that exacerbate the condition are desirable. It would be far more cost effective and much better for the patient's health if chronic heart failure could be managed and controlled by the routine or controlled release administration of appropriate drug therapy rather than by hospital treatment upon the manifestation of acute symptoms.